ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.749T>C (p.Val250Ala) (rs587781275)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128926 SCV000172796 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
GeneDx RCV000656890 SCV000211262 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.749T>C at the cDNA level, p.Val250Ala (V250A) at the protein level, and results in the change of a Valine to an Alanine (GTC>GCC). This variant has been observed in an individual with prostate cancer, another with ovarian cancer, and at least one high-risk individual with breast and/or ovarian cancer (Lu 2015, Maxwell 2016). It was also identified in a prostate cancer tumor sample bearing more confirmed somatic mutations than average, suggesting a mutator phenotype (Taylor 2010). MSH6 Val250Ala was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located within the nuclear localization signals (Gassman 2011). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Val250Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168003 SCV000218654 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 250 of the MSH6 protein (p.Val250Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs587781275, ExAC 0.003%). This variant has been reported in an individual with ovarian cancer, an individual with prostate cancer (PMID: 26689913), and an individual with colorectal cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 140780). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000410809 SCV000488935 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-07-22 criteria provided, single submitter clinical testing
Color RCV000128926 SCV000685520 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202238 SCV000917767 uncertain significance not specified 2019-05-24 criteria provided, single submitter clinical testing Variant summary: MSH6 c.749T>C (p.Val250Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.749T>C has been reported in the literature in two individuals affected with Pancreatic Adenocarcinoma or Ovarian Carcinoma respectively in a study that searched for candidate germline cancer predisposition variants in the exome sequence data from 4,034 cancer patients across 12 diverse cancer types (Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202238 SCV000257306 uncertain significance not specified no assertion criteria provided clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761137 SCV000891053 uncertain significance B lymphoblastic leukemia lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) 2016-10-31 no assertion criteria provided clinical testing

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